Abstact

Presynaptic 5-HT(1A)R autoreceptors predominantly signal through G(i3) protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic heteroreceptors mainly couple to G(o), which promotes antidepressant responses. However, selectively activating heteroreceptors while bypassing the negative feedback induced by autoreceptors remains a significant challenge. Here, we characterized the G(i/o) subtype signaling profiles of 5-HT(1A)R and determined its structures in complex with six agonists and three distinct G(i/o) family proteins: G(oA), G(i3), and G(z). Combined with functional analysis, we elucidated the mechanisms underlying diverse agonist recognition modes and G(i/o) subtype signaling selectivity of 5-HT(1A)R. Furthermore, we designed a pathway-selective agonist, TMU4142, which exhibits high G(oA) activity while minimizing G(i3) activation. Remarkably, TMU4142 demonstrated rapid antidepressant-like effects in a mouse model of depression. Collectively, these findings suggest that distinguishing heteroreceptors from autoreceptors based on their distinct downstream G(i/o) signaling pathways could be a promising strategy to develop fast-acting antidepressants.